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1.  Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease 
Scientific Reports  2015;5:8096.
Non-alcoholic fatty liver disease (NAFLD) has recently been considered to be under the influence of the gut microbiota, which might exert toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. In this study, the composition of the gut microbiota in NAFLD patients and healthy subjects was determined via 16S ribosomal RNA Illumina next-generation sequencing. Among those taxa displaying greater than 0.1% average abundance in all samples, five genera, including Alistipes and Prevotella, were significantly more abundant in the gut microbiota of healthy subjects compared to NAFLD patients. Alternatively, Escherichia, Anaerobacter, Lactobacillus and Streptococcus were increased in the gut microbiota of NAFLD patients compared to healthy subjects. In addition, decreased numbers of CD4+ and CD8+ T lymphocytes and increased levels of TNF-α, IL-6 and IFN-γ were detected in the NAFLD group compared to the healthy group. Furthermore, irregularly arranged microvilli and widened tight junctions were observed in the gut mucosa of the NAFLD patients via transmission electron microscopy. We postulate that aside from dysbiosis of the gut microbiota, gut microbiota-mediated inflammation of the intestinal mucosa and the related impairment in mucosal immune function play an important role in the pathogenesis of NAFLD.
PMCID: PMC4314632  PMID: 25644696
2.  Primary adenoid cystic carcinoma of the lung: Clinicopathological features, treatment and results 
Oncology Letters  2015;9(3):1475-1481.
Adenoid cystic carcinoma of the lung (ACCL) is a rare salivary gland-type malignant neoplasm that occurs infrequently as a primary tumor of the airway. Owing to its low incidence, the clinicopathological features, immunohistochemical expression spectrum, treatment and long-term survival have not been fully elucidated. The present study retrospectively assessed the clinical features, immunohistochemical characters, treatment strategy and long-term survival of 34 patients diagnosed with ACCL at the Beijing Chest Hospital, Capital Medical University (Beijing, China) between January 1993 and June 2014. ACCL tended to occur in younger patients, with an approximate male/female ratio of 1:1. The majority of ACCL arose from the central airway. Positive immunochemical staining was found in wide-spectrum keratin (n=17), cytokeratin (CK)7 (n=11), p63 (11/12), S-100 (7/8), vimentin (10/12) and smooth muscle actin (6/9). No staining of thyroid transcription factor-1 (0/14), synaptophysin (0/7), cluster of differentiation 56 (0/7), CK20 (0/4) or chromogranin A (0/4) was observed. In the operable group (n=26), the addition of adjuvant radiotherapy to a positive margin resection (R1 resection) obtained long-term survival times equivalent to that found in patients with a negative margin resection (R0 resection). No significant survival benefit from post-operative radiotherapy was observed in the R0 resection group. For advanced cases, palliative radiotherapy and chemotherapy did not work efficiently. In addition, epidermal growth factor receptor mutation was a rare event in the ACCL patients. The results indicated that surgical resection is the optimal management for ACCL whenever feasible. Adjuvant radiotherapy with R1 resection is able to obtain long-term survival times comparable with those found using an R0 resection. The recommendation of post-operative radiotherapy for all patients with ACCL undergoing resection appears controversial. Owing to a poor response to radiotherapy and chemotherapy, more focus should be placed on the study of advanced ACCL in order to improve overall survival.
PMCID: PMC4314995  PMID: 25663934
adenoid cystic carcinoma; lung; clinicopathology; immunohistochemistry; treatment; survival
3.  Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis 
The Journal of Clinical Investigation  2014;124(10):4363-4374.
The NF-κB signaling pathway is implicated in various inflammatory diseases, including rheumatoid arthritis (RA); therefore, inhibition of this pathway has the potential to ameliorate an array of inflammatory diseases. Given that NF-κB signaling is critical for many immune cell functions, systemic blockade of this pathway may lead to detrimental side effects. siRNAs coupled with a safe and effective delivery nanoplatform may afford the specificity lacking in systemic administration of small-molecule inhibitors. Here we demonstrated that a melittin-derived cationic amphipathic peptide combined with siRNA targeting the p65 subunit of NF-κB (p5RHH-p65) noncovalently self-assemble into stable nanocomplexes that home to the inflamed joints in a murine model of RA. Specifically, administration of p5RHH-p65 siRNA nanocomplexes abrogated inflammatory cytokine expression and cellular influx into the joints, protected against bone erosions, and preserved cartilage integrity. The p5RHH-p65 siRNA nanocomplexes potently suppressed early inflammatory arthritis without affecting p65 expression in off-target organs or eliciting a humoral response after serial injections. These data suggest that this self-assembling, largely nontoxic platform may have broad utility for the specific delivery of siRNA to target and limit inflammatory processes for the treatment of a variety of diseases.
PMCID: PMC4191028  PMID: 25157820
4.  Complementary Roles of Squamous Cell Carcinoma Antigen and 18F-FDG PET/CT in Suspected Recurrence of Cervical Squamous Cell Cancer 
Journal of Cancer  2015;6(3):287-291.
Purpose: To assess the clinical value of FDG PET/CT and evaluate the complementary roles of serum squamous cell carcinoma antigen (SCCAg) and FDG PET/CT in the diagnosis of suspected recurrent of cervical squamous cell cancer. Methods: Serum SCCAg levels were retrospectively reviewed in patients previously treated for cervical squamous cell carcinoma, who had suspected recurrence of cervical cancer and who had undergone FDG PET/CT scans. The clinical impact of elevated SCCAg (>1.5 ng/ml) and negative SCCAg (≤1.5 ng/ml) levels were analyzed based on the results of PET/CT and final diagnosis. Results: The overall patient-based sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of PET/CT for the detection of tumor recurrence or malignancy were 100% (86/86), 80.8% (21/26), 95.5% (107/112), 94.5% (86/91) and 100% (21/21), respectively. Of the 112 patients included in this study, recurrence or malignancy was detected by PET/CT in 62 of the 64 patients with elevated SCCAg, compared to 24 of the 48 patients with negative SCCAg levels. The overall patient-based PPV, NPV, sensitivity and accuracy of SCCAg for the detection of tumor recurrence or malignancy were 96.9% (62/64), 50% (24/48), 72.1% (62/86) and 76.8% (86/112), respectively. The five false-positive PET/CT results were all associated with patients with negative SCCAg levels. The PPV of positive PET/CT-associated elevated SCCAg for the detection of tumor recurrence or malignancy was 100% (62/62). The NPV of negative SCCAg-associated negative PET/CT was 100% (19/19). Conclusions: Serum SCCAg evaluation and FDG PET/CT imaging can be complementary techniques in cases of suspected recurrent cervical squamous cancer. Positive PET/CT with elevated SCCAg can predict recurrence. Although PET/CT cannot confidently be deferred due to a negative SCCAg test, the possibility of a false-positive PET/CT in those cases may have diagnostic importance.
PMCID: PMC4317765  PMID: 25663947
Squamous cell carcinoma antigen; Cervical squamous cancer; Recurrence; FDG PET/CT; False positive
5.  High-level SAE2 promotes malignant phenotype and predicts outcome in gastric cancer 
Background: The SUMO pathway has been shown to play an important role in tumorigenesis. This report analyzed the involvement of the sole SUMO-Activating Enzyme Subunit 2 (SAE2) in human gastric cancer (GC) progression and prognosis. Methods: Expression of SAE2 was examined by Quantigene Plex, western blotting and immunohistochemistry. The expression of SAE2 and c-MYC were detected in parallel in 276 cases. The molecular mechanisms of SAE2 expression and its effects on cell growth, colony formation, migration and invasion were also explored by CCK8 assay, colony formation experiment, transwell chamber assay with or without matrigel, immunoprecipitation and in vivo tumorigenesis and tumor metastasis. Results: SAE2 was markedly overexpressed in GC cell lines and primary tumor samples of GC, and significantly correlated with deeper tumor depth, distant metastasis, higher pathological stage and stratified survival in human GC. SAE2 positivity was independently associated with a worse outcome in multivariate analysis. Knockdown of SAE2 expression inhibited the proliferation, migration, and invasion of SAE2-overexpressing GC cells. Consistent with the in vitro results, down-regulation of SAE2 in human GC BGC823 cells significantly reduced the tumorigenic and metastatic potential of the cells in vivo. SAE2 protein was significantly associated with the higher expression of c-MYC in primary GC tissues. Moreover, FoxM1 was SUMOylated in GC and that inhibition of SAE2 resulted in a decrease in SUMO1-FoxM1 levels compared with those in the controls. Conclusions: These findings suggest that SAE2 has a pivotal role in the aggressiveness of GC, and highlight its usefulness as a prognostic factor in GC.
PMCID: PMC4300690  PMID: 25628926
SAE2; gastric cancer; prognosis; FoxM1; c-MYC
6.  Relationship between red cell distribution width and serum uric acid in patients with untreated essential hypertension 
Scientific Reports  2014;4:7291.
We assessed whether red cell distribution width (RDW) is associated with serum uric acid (UA) level in a group of 512 patients with newly diagnosed hypertension, recruited in Beijing. Patients were divided into high uric acid group and low uric acid group according to the median (334.9 μmol/L) of serum uric acid. Compared with the low uric acid group, the patients with high uric acid had higher red blood cell count (P < 0.001) and RDW (P = 0.032). The multiple linear regression analysis showed that RDW (P = 0.001) was positively correlated with uric acid level after the adjustment of related factors. Stepwise multiple logistic regression model confirmed that RDW (odds ratio: OR = 1.75) was independent determinants of high serum uric acid as well as sex (OR = 6.03), triglycerides (OR = 1.84), and Blood Urea Nitrogen (BUN, OR = 1.30). RDW may be independently associated with serum UA level in patients with newly diagnosed hypertension. To firmly establish the causal role of RDW in the incidence of high uric acid level among hypertensive patients, large cohort studies are needed.
PMCID: PMC4252898  PMID: 25464864
7.  Natural history of pulmonary function in collagen VI-related myopathies 
Brain  2013;136(12):3625-3633.
The spectrum of clinical phenotypes associated with a deficiency or dysfunction of collagen VI in the extracellular matrix of muscle are collectively termed ‘collagen VI-related myopathies’ and include Ullrich congenital muscular dystrophy, Bethlem myopathy and intermediate phenotypes. To further define the clinical course of these variants, we studied the natural history of pulmonary function in correlation to motor abilities in the collagen VI-related myopathies by analysing longitudinal forced vital capacity data in a large international cohort. Retrospective chart reviews of genetically and/or pathologically confirmed collagen VI-related myopathy patients were performed at 10 neuromuscular centres: USA (n = 2), UK (n = 2), Australia (n = 2), Italy (n = 2), France (n = 1) and Belgium (n = 1). A total of 486 forced vital capacity measurements obtained in 145 patients were available for analysis. Patients at the severe end of the clinical spectrum, conforming to the original description of Ullrich congenital muscular dystrophy were easily identified by severe muscle weakness either preventing ambulation or resulting in an early loss of ambulation, and demonstrated a cumulative decline in forced vital capacity of 2.6% per year (P < 0.0001). Patients with better functional abilities, in whom walking with/without assistance was achieved, were initially combined, containing both intermediate and Bethlem myopathy phenotypes in one group. However, one subset of patients demonstrated a continuous decline in pulmonary function whereas the other had stable pulmonary function. None of the patients with declining pulmonary function attained the ability to hop or run; these patients were categorized as intermediate collagen VI-related myopathy and the remaining patients as Bethlem myopathy. Intermediate patients had a cumulative decline in forced vital capacity of 2.3% per year (P < 0.0001) whereas the relationship between age and forced vital capacity in patients with Bethlem myopathy was not significant (P = 0.1432). Nocturnal non-invasive ventilation was initiated in patients with Ullrich congenital muscular dystrophy by 11.3 years (±4.0) and in patients with intermediate collagen VI-related myopathy by 20.7 years (±1.5). The relationship between maximal motor ability and forced vital capacity was highly significant (P < 0.0001). This study demonstrates that pulmonary function profiles can be used in combination with motor function profiles to stratify collagen VI-related myopathy patients phenotypically. These findings improve our knowledge of the natural history of the collagen VI-related myopathies, enabling proactive optimization of care and preparing this patient population for clinical trials.
PMCID: PMC3859224  PMID: 24271325
collagen VI-related myopathies; natural history; forced vital capacity; optimization of care; outcome measure
8.  Antihypertensive therapy with nicardipine for patients with aortic disease is associated with more esmolol usage than urapidil 
Journal of Thoracic Disease  2014;6(12):1765-1771.
Acute aortic disease is a common but challenging entity in clinical practice. Titration the blood pressure and heart rate to a target level is of paramount importance in the acute phase regardless of whether the patient will undergo a surgery or not eventually. In addition to the initially intravenous β-blockers, parenteral infusion of nicardipine and urapidil are the most common used antihypertensive therapy currently in mainland China. However, few empirical data was available with respect to the different effect on patients’ outcome of the two antihypertensive strategies. Specifically given the deleterious reflex tachycardia of vasodilators which may increase force of ventricular contraction and potentially worsen aortic disease. Therefore, this study was aimed to evaluate the difference of the abovementioned two antihypertensive strategies on the outcome of patients with aortic disease.
All patients with new diagnosed aortic diseases presented to our hospitals from January 1, 2013 to June 30, 2014 were retrospectively reviewed. The antihypertensive strategies and their association with patients’ outcomes were evaluated with logistics regression.
A total of 120 patients with new diagnosed aortic disease were included in the study. Of them, 47 patients received urapidil while 73 patients received nicardipine antihypertensive therapy. Patients with nicardipine were more quickly to reach the target blood pressure level than those treated with urapidil (median, 18 vs. 35 min, P=0.024). After adjustment for patient demographics, co-morbidity, involved extend of aorta, interventional strategies, antihypertensive therapy with nicardipine (with urapidil as reference) for patients with aortic disease was significantly associated with high esmolol cost [odds ratio (OR): 6.2, 95% confidence interval (CI), 1.8-21.6, P=0.004] and longer ICU length of stay (LOS) (OR: 3.9, 95% CI, 1.5-10.3, P=0.006). However, there was no significant correlation between nicardipine use and ICU mortality (OR: 0.3; 95% CI, 0.1-1.4, P=0.123).
Although nicardipine achieved the target blood pressure level more quickly than urapidil for patients with aortic disease, it was associated with more esmolol use and longer ICU LOS.
PMCID: PMC4283351  PMID: 25589971
Aortic disease; antihypertensive therapy; nicardipine; urapidil
9.  A Systems Genetics Approach Identifies CXCL14, ITGAX, and LPCAT2 as Novel Aggressive Prostate Cancer Susceptibility Genes 
PLoS Genetics  2014;10(11):e1004809.
Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL) mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ) F2 intercross males (n = 228), which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ) F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322) were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A) were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2) harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such approaches will facilitate the identification of novel germline factors driving aggressive disease susceptibility and allow for new insights into these deadly forms of prostate cancer.
Author Summary
Prostate cancer is a remarkably common disease, and in 2014 it is estimated that it will account for 27% of new cancer cases in men in the US. However, less than 13% those diagnosed will succumb to prostate cancer, with most men dying from unrelated causes. The tests used to identify men at risk of fatal prostate cancer are inaccurate, which leads to overtreatment, unnecessary patient suffering, and represents a significant public health burden. Many studies have shown that hereditary genetic variation significantly alters susceptibility to fatal prostate cancer, although the identities of genes responsible for this are mostly unknown. Here, we used a mouse model of prostate cancer to identify such genes. We introduced hereditary genetic variation into this mouse model through breeding, and used a genetic mapping technique to identify 35 genes associated with aggressive disease. The levels of three of these genes were consistently abnormal in human prostate cancers with a more aggressive disease course. Additionally, hereditary differences in these same three genes were associated with markers of fatal prostate cancer in men. This approach has given us unique insights into how hereditary variation influences fatal forms of prostate cancer.
PMCID: PMC4238980  PMID: 25411967
11.  Evaluation of mean platelet volume in patients with hepatitis B virus infection 
Objective: Mean platelet volume (MPV), which is determined by a routine complete blood count, is a parameter that is usually overlooked by clinicians. The present study was designed to investigate the association between MPV and different disease states in patients with hepatitis B virus (HBV) infection. Methods: A total of 120 patients, including 17 with acute hepatitis B (AHB), 62 with chronic hepatitis B (CHB), and 41 with chronic severe hepatitis B (CSHB), as well as 58 healthy controls (HCs) were enrolled in the study. At study entry, blood samples were collected from all subjects to examine liver function and renal function, determine the international normalized ratio and perform routine hematological tests. Results: We demonstrated that MPV was significantly increased in CSHB and CHB patients compared with HCs and AHB patients (all P<0.05). Among the patient groups, the CSHB patients had the highest MPV. Increased MPV was clinically associated with severe liver disease. Conclusions: MPV is significantly increased in chronic HBV-infected patients and is associated with disease severity; thus, it may serve as an important biomarker.
PMCID: PMC4276190  PMID: 25550932
Mean platelet volume; hepatitis B virus infection; biomarker
12.  RhoA and Membrane Fluidity Mediates the Spatially Polarized Src/FAK Activation in Response to Shear Stress 
Scientific Reports  2014;4:7008.
While Src plays crucial roles in shear stress-induced cellular processes, little is known on the spatiotemporal pattern of high shear stress (HSS)-induced Src activation. HSS (65 dyn/cm2) was applied on bovine aortic endothelial cells to visualize the dynamic Src activation at subcellular levels utilizing a membrane-targeted Src biosensor (Kras-Src) based on fluorescence resonance energy transfer (FRET). A polarized Src activation was observed with higher activity at the side facing the flow, which was enhanced by a cytochalasin D-mediated disruption of actin filaments but inhibited by a benzyl alcohol-mediated enhancement of membrane fluidity. Further experiments revealed that HSS decreased RhoA activity, with a constitutively active RhoA mutant inhibiting while a negative RhoA mutant enhancing the HSS-induced Src polarity. Cytochalasin D can restore the polarity in cells expressing the active RhoA mutant. Further results indicate that HSS stimulates FAK activation with a spatial polarity similar to Src. The inhibition of Src by PP1, as well as the perturbation of RhoA activity and membrane fluidity, can block this HSS-induced FAK polarity. These results indicate that the HSS-induced Src and subsequently FAK polarity depends on the coordination between intracellular tension distribution regulated by RhoA, its related actin structures and the plasma membrane fluidity.
PMCID: PMC4228346  PMID: 25387906
13.  Clinical Application of Partial Splenic Embolization 
The Scientific World Journal  2014;2014:961345.
Partial splenic embolization (PSE) is one of the intra-arterial therapeutic approaches of diseases. With the development of interventional radiology, the applications of PSE in clinical practice are greatly extended, while various materials are developed for embolization use. Common indications of PSE include hypersplenism with portal hypertension, hereditary spherocytosis, thalassemia, autoimmune hemolytic anemia, splenic trauma, idiopathic thrombocytopenic purpura, splenic hemangioma, and liver cancer. It is also performed to exclude splenic artery aneurysms from the parent vessel lumen and prevent aneurysm rupture, to treat splenic artery steal syndrome and improve liver perfusion in liver transplant recipients, and to administer targeted treatment to areas of neoplastic disease in the splenic parenchyma. Indicators of the therapeutic effect evaluation of PSE comprise blood routine test, changes in hemodynamics and in splenic volume. Major complications of PSE include the pulmonary complications, severe infection, damages of renal and liver function, and portal vein thrombosis. The limitations of PSE exist mainly in the difficulties in selecting the arteries to embolize and in evaluating the embolized volume.
PMCID: PMC4235844  PMID: 25538966
14.  Cyclin-Dependent Kinase 5 in the Ventral Tegmental Area Regulates Depression-Related Behaviors 
The Journal of Neuroscience  2014;34(18):6352-6366.
Dopamine neurons in the ventral tegmental area (VTA) govern reward and motivation and dysregulated dopaminergic transmission may account for anhedonia and other symptoms of depression. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that regulates a broad range of brain functions through phosphorylation of a myriad of substrates, including tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis. We investigated whether and how Cdk5 activity in VTA dopamine neurons regulated depression-related behaviors in mice. Using the Cre/LoxP system to selectively delete Cdk5 in the VTA or in midbrain dopamine neurons in Cdk5loxP/loxP mice, we showed that Cdk5 loss of function in the VTA induced anxiety- and depressive-like behaviors that were associated with decreases in TH phosphorylation at Ser31 and Ser40 in the VTA and dopamine release in its target region, the nucleus accumbens. The decreased phosphorylation of TH at Ser31 was a direct effect of Cdk5 deletion, whereas decreased phosphorylation of TH at Ser40 was likely caused by impaired cAMP/protein kinase A (PKA) signaling, because Cdk5 deletion decreased cAMP and phosphorylated cAMP response element-binding protein (p-CREB) levels in the VTA. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology, we showed that selectively increasing cAMP levels in VTA dopamine neurons increased phosphorylation of TH at Ser40 and CREB at Ser133 and reversed behavioral deficits induced by Cdk5 deletion. The results suggest that Cdk5 in the VTA regulates cAMP/PKA signaling, dopaminergic neurotransmission, and depression-related behaviors.
PMCID: PMC4004818  PMID: 24790206
cAMP; Cdk5; depression; dopamine; DREADD; tyrosine hydroxylase
15.  CD30 Expression in High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndromes 
We assessed for CD30 expression in patients with acute myeloid leukemia (AML) or high-grade myelodysplastic syndrome (MDS) to examine the possibility that anti-CD30 could be targeted therapy in these patients.
Multicolor flow cytometry immunophenotypic analysis was performed on bone marrow aspirates of 135 AML/MDS patients and peripheral blood (PB) samples in a subset of 33 patients. Immunohistochemistry was performed on BM aspirate clot specimens of 84 patients.
The median patient age was 63 years (range, 13–92). One hundred and two (75%) patients had refractory or recurrent disease, and 68 (50%) had high-risk cytogenetics. Overall, the median percentage of blasts positive for CD30 was 14% (range, 0–91). Using an arbitrary 20% cutoff, 49 (36%) patients were considered to have CD30-expression. Monocytic cells, either mature or immature, were consistently negative for CD30. Therefore, CD30 expression was less in AML with monocytic differentiation (P=0.006). Patients with persistent disease who had been actively treated had a higher level of CD30 expression than untreated patients (p=0.031). In paired samples, CD30 expression was consistently higher in BM blasts than PB blasts (p=0.002). Immunohistochemistry demonstrated CD30 expression by myeloblasts in a subset of patients, but reactivity was generally weaker and focal compared.
CD30 is expressed by myeloblasts in a substantial subset of AML/MDS patients. As the study group was composed mostly of high-risk AML/MDS patients in whom very few treatment options are available, these data raise the possibility that anti-CD30- targeted therapy could be a potential option for this patient group.
PMCID: PMC4188388  PMID: 23313069
CD30; acute myeloid leukemia; myelodysplastic syndromes; flow cytometry; immunohistochemistry
16.  Quantifying spectral changes experienced by plasmonic nanoparticles in a cellular environment to inform biomedical nanoparticle design 
Nanoscale Research Letters  2014;9(1):454.
Metal nanoparticles (NPs) scatter and absorb light in precise, designable ways, making them agile candidates for a variety of biomedical applications. When NPs are introduced to a physiological environment and interact with cells, their physicochemical properties can change as proteins adsorb on their surface and they agglomerate within intracellular endosomal vesicles. Since the plasmonic properties of metal NPs are dependent on their geometry and local environment, these physicochemical changes may alter the NPs' plasmonic properties, on which applications such as plasmonic photothermal therapy and photonic gene circuits are based. Here we systematically study and quantify how metal NPs' optical spectra change upon introduction to a cellular environment in which NPs agglomerate within endosomal vesicles. Using darkfield hyperspectral imaging, we measure changes in the peak wavelength, broadening, and distribution of 100-nm spherical gold NPs' optical spectra following introduction to human breast adenocarcinoma Sk-Br-3 cells as a function of NP exposure dose and time. On a cellular level, spectra shift up to 78.6 ± 23.5 nm after 24 h of NP exposure. Importantly, spectra broaden with time, achieving a spectral width of 105.9 ± 11.7 nm at 95% of the spectrum's maximum intensity after 24 h. On an individual intracellular NP cluster (NPC) level, spectra also show significant shifting, broadening, and heterogeneity after 24 h. Cellular transmission electron microscopy (TEM) and electromagnetic simulations of NPCs support the trends in spectral changes we measured. These quantitative data can help guide the design of metal NPs introduced to cellular environments in plasmonic NP-mediated biomedical technologies.
PMCID: PMC4164329  PMID: 25258596
Nano-bio interactions; Plasmon resonance; Hyperspectral imaging; Gold nanoparticles; Cells; Spectral analysis; Nanomedicine
17.  Interference between Conscious and Unconscious Facial Expression Information 
PLoS ONE  2014;9(8):e105156.
There is ample evidence to show that many types of visual information, including emotional information, could be processed in the absence of visual awareness. For example, it has been shown that masked subliminal facial expressions can induce priming and adaptation effects. However, stimulus made invisible in different ways could be processed to different extent and have differential effects. In this study, we adopted a flanker type behavioral method to investigate whether a flanker rendered invisible through Continuous Flash Suppression (CFS) could induce a congruency effect on the discrimination of a visible target. Specifically, during the experiment, participants judged the expression (either happy or fearful) of a visible face in the presence of a nearby invisible face (with happy or fearful expression). Results show that participants were slower and less accurate in discriminating the expression of the visible face when the expression of the invisible flanker face was incongruent. Thus, facial expression information rendered invisible with CFS and presented a different spatial location could enhance or interfere with consciously processed facial expression information.
PMCID: PMC4146517  PMID: 25162153
18.  Systematic Genetic Analysis Identifies Cis-eQTL Target Genes Associated with Glioblastoma Patient Survival 
PLoS ONE  2014;9(8):e105393.
Prior expression quantitative trait locus (eQTL) studies have demonstrated heritable variation determining differences in gene expression. The majority of eQTL studies were based on cell lines and normal tissues. We performed cis-eQTL analysis using glioblastoma multiforme (GBM) data sets obtained from The Cancer Genome Atlas (TCGA) to systematically investigate germline variation’s contribution to tumor gene expression levels. We identified 985 significant cis-eQTL associations (FDR<0.05) mapped to 978 SNP loci and 159 unique genes. Approximately 57% of these eQTLs have been previously linked to the gene expression in cell lines and normal tissues; 43% of these share cis associations known to be associated with functional annotations. About 25% of these cis-eQTL associations are also common to those identified in Breast Cancer from a recent study. Further investigation of the relationship between gene expression and patient clinical information identified 13 eQTL genes whose expression level significantly correlates with GBM patient survival (p<0.05). Most of these genes are also differentially expressed in tumor samples and organ-specific controls (p<0.05). Our results demonstrated a significant relationship of germline variation with gene expression levels in GBM. The identification of eQTLs-based expression associated survival might be important to the understanding of genetic contribution to GBM cancer prognosis.
PMCID: PMC4136869  PMID: 25133526
19.  FAK and paxillin dynamics at focal adhesions in the protrusions of migrating cells 
Scientific Reports  2014;4:6024.
Cell migration requires the fine spatiotemporal integration of many proteins that regulate the fundamental processes that drive cell movement. Focal adhesion (FA) dynamics is a continuous process involving coordination between FA and actin cytoskeleton, which is essential for cell migration. We studied the spatiotemporal relationship between the dynamics of focal adhesion kinase (FAK) and paxillin at FAs in the protrusion of living endothelial cells. Concurrent dual-color imaging showed that FAK was assembled at FA first, which was followed by paxillin recruitment to the FA. By tracking and quantifying FAK and paxillin in migrating cells, the normalized FAK/Paxillin fluorescence intensity (FI) ratio is > 1 (≈4 fold) at cell front, ≈1 at cell center, and < 1 at cell rear. The significantly higher FAK FI than paxillin FI at cell front indicates that the assembly of FAK-FAs occurs ahead of paxillin at cell front. To determine the time difference between the assemblies of FAK and paxillin at nascent FAs, FAs containing both FAK and paxillin were quantified by image analysis and time correlation. The results show that FAK assembles at the nascent FAs earlier than paxillin in the protrusions at cell front.
PMCID: PMC4129417  PMID: 25113375
20.  Giant uterine artery pseudoaneurysm after a missed miscarriage termination in a cesarean scar pregnancy 
BMC Women's Health  2014;14:89.
Uterine artery pseudoaneurysms are dangerous and can lead to severe hemorrhage. We report an uncommon cause of a giant pseudoaneurysm in a missed miscarriage in a woman with a cesarean scar pregnancy.
Case presentation
The patient was a 25-year-old Chinese woman with a missed miscarriage in a cesarean scar pregnancy. Curettage was performed under ultrasound monitoring. A uterine artery pseudoaneurysm measuring 71 × 44 × 39 mm was detected the next day by Doppler ultrasonography. While waiting for admittance to an advanced institution to undergo embolization treatment, the pseudoaneurysm ruptured spontaneously. The subsequent severe hemorrhage necessitated hysterectomy.
A delay in diagnosis of uterine artery pseudoaneurysms may result from a long period between the curettage and follow-up examination. Ultrasound and Doppler ultrasonography should be performed repeatedly at short intervals to rule out them, especially in cesarean scar pregnancies. For a giant uterine artery pseudoaneurysm, interventional embolization might be the first treatment choice. If time allows, intra-operative ligation of the feeding vessels should be attempted before any decision to perform a hysterectomy is made. However, hysterectomy remains a possibility when severe bleeding occurs.
PMCID: PMC4118154  PMID: 25070087
Uterus; Pseudoaneurysm; Ultrasound; Missed miscarriage; Cesarean scar pregnancy
21.  Light chain multiple myeloma, clinic features, responses to therapy and survival in a long-term study 
We intended to investigate the long-term clinical characteristics, responses to therapy and survival in patients with lightchain multiple myeloma (MM).
Ninety-six patients were enrolled into the study. There were 42 κ-chain MM patients and 54 λ-chain MM patients. All the patients werestage III in the Durie-Salmonstaging system. Among them, 66 patients received Velcade (bortezomib) treatment and the other 30 did not.
The main symptoms of these patients included bone pain (77.1%), weakness and fatigue (12.5%), foamy urine (8.3%) and extramedullaryplasmocytomas (33.3%). The overall response rate (ORR) was 95.5% in patients treated with Velcade and 60%in the patients without. The median survival times were 23 months in patients treated with Velcade and 12 months in patients without. The median time of progression-free survival (PFS) was nine months in patients treated with Velcade and five months in patients without. The one-year PFS and two-year PFS were 37% and 25%, 27% and 9% for patients treated with Velcade, or without, respectively. The three-year overall survival (OS) and five-year OS were 33% and 24%, 28% and 9% for patients treated with Velcade, or without, respectively. There was no significance in OS between the two groups (P = 0.335). But there was significant difference in PFS between the two groups (P = 0.036).
Our long-term study demonstrated that patients with lightchain myeloma appeared to have more aggressive disease courses and poor outcomes, which could be improved by treatment with Velcade.
PMCID: PMC4237965  PMID: 25070574
Multiple myeloma; Light chain myeloma; Velcade; Survival
22.  Clinical significance of serum and tumor tissue endostatin evaluation in operable non-small cell lung cancer 
Biomedical Reports  2014;2(6):898-904.
Endostatin, as the most potential antiangiogenic factor, is a naturally occurring fragment of collagen XVIII in bloodstream capable of inhibiting tumor growth and metastasis. This study was conducted to explore the clinical value of endostatin in serum and tumor tissue in patients with operable non-small cell lung cancer (NSCLC). ELISA and immunohistochemistry were applied to detect the expression of endostatin in serum and tumor tissue in 105 patient-matched operable NSCLC patients. The serum level of endostatin was significantly higher in NSCLC patients than healthy individuals (P=0.0018). Cases with poorer differentiation showed a higher endostatin serum level (P=0.008). There was no significant correlation between tumor tissue expression and clinical parameters, such as TNM stage, differentiation degree, histological type and lymph node invasion status. A stronger expression of endostain in tumor tissue was associated with a higher serum level (r=0.223). The univariate and multivariate analyses with Cox proportional hazards model for overall survival showed that tumor stage and node status were independent prognostic factors, whereas neither endostatin levels in serum nor in tumor tissue showed potential in predicting the long-term survival of operable NSCLC patients. In conclusion, the results observed in the present study did not support the prediction of overall survival in operable NSCLC based on the expression levels of endostatin in serum and tumor tissue.
PMCID: PMC4179775  PMID: 25279166
non-small cell lung cancer; endostatin; angiogenesis; prognosis
23.  A deficiency of apoptosis inducing factor (AIF) in Harlequin mouse heart mitochondria paradoxically reduces ROS generation during ischemia-reperfusion 
Background and Aims: AIF (apoptosis inducing factor) is a flavin and NADH containing protein located within mitochondria required for optimal function of the respiratory chain. AIF may function as an antioxidant within mitochondria, yet when released from mitochondria it activates caspase-independent cell death. The Harlequin (Hq) mouse has a markedly reduced content of AIF, providing an experimental model to query if the main role of AIF in the exacerbation of cell death is enhanced mitochondrial generation of reactive oxygen species (ROS) or the activation of cell death programs. We asked if the ROS generation is altered in Hq heart mitochondria at baseline or following ischemia-reperfusion (IR).
Methods: Buffer perfused mouse hearts underwent 30 min ischemia and 30 min reperfusion. Mitochondrial function including oxidative phosphorylation and H2O2 generation was measured. Immunoblotting was used to determine the contents of AIF and PAR [poly(ADP-ribose)] in cell fractions.
Results: There were no differences in the release of H2O2 between wild type (WT) and Hq heart mitochondria at baseline. IR increased H2O2 generation from WT but not from Hq mitochondria compared to corresponding time controls. The complex I activity was decreased in WT but not in Hq mice following IR. The relocation of AIF from mitochondria to nucleus was increased in WT but not in Hq mice. IR activated PARP-1 only in WT mice. Cell injury was decreased in the Hq mouse heart following in vitro IR.
Conclusion: A deficiency of AIF within mitochondria does not increase ROS production during IR, indicating that AIF functions less as an antioxidant within mitochondria. The decreased cardiac injury in Hq mouse heart accompanied by less AIF translocation to the nucleus suggests that AIF relocation, rather than the AIF content within mitochondria, contributes to cardiac injury during IR.
PMCID: PMC4106194  PMID: 25101006
reactive oxygen species; electron transport chain; apoptosis; poly(ADP-ribose)
24.  Cerium promotes bone marrow stromal cells migration and osteogenic differentiation via Smad1/5/8 signaling pathway 
Cerium (Ce), one of the lanthanides (Ln), displays a variety of biochemical and physiological effects. However, the potential effect and mechanism of Ce on bone metabolism are not well understood. In this study, we investigated the putative role of Ce in regulating the migration and osteogenic differentiation of bone marrow stromal cells (BMSCs) and the underlying mechanism. The results indicated that Ce promoted BMSCs viability and ALP activity at lower concentrations (0.001 μM), and decreased the viability and ALP activity of BMSCs at higher concentrations (10 μM). Ce could also affect the expression of osteogenic transcription factors (Runx2, Satb2 and OCN) in BMSCs. Our results also showed that Ce promoted migration of BMSCs by increasing SDF-1 mRNA expression. As the Smad-dependent BMP signaling pathway plays an important role in migration and osteogenic differentiation of BMSCs, our results are in agreement with Ce promoting the phosphorylation of Smad1/5/8 and translocating to the nucleus by increase BMP2 expression. The activity of p-Smad1/5/8 increased SDF-1 and Runx2 expression level in BMSCs. In conclusion, our results support the notion that Ce promoted migration and osteogenic differentiation of BMSCs by Smad1/5/8 signaling pathway.
PMCID: PMC4152115  PMID: 25197425
Ce; BMSCs; migration; osteogenic differentiation; Smad1/5/8 signaling pathway
25.  The Impact of Social Factors on Human Immunodeficiency Virus and Hepatitis C Virus Co-Infection in a Minority Region of Si-Chuan, the People's Republic of China: A Population-Based Survey and Testing Study 
PLoS ONE  2014;9(7):e101241.
While many human immunodeficiency virus (HIV) studies have been performed in Liangshan, most were focused only on HIV infection and based on a sampling survey. In order to fully understand HIV and hepatitis C virus (HCV) prevalence and related risk factors in this region, this study implemented in 2009, included a survey, physical examination, HIV and HCV test in two towns.
All residents in two towns of the Butuo county were provided a physical examination and blood tests for HIV and HCV, and then followed by an interview for questionnaire.
In total, 10,104 residents (92.4%) were enrolled and 9,179 blood samples were collected for HIV and HCV testing, 6,072 were from individuals >14 years old. The rates of HIV, HCV, and HIV/HCV co-infection were 11.4%, 14.0%, and 7.7%, respectively for >14-year-old residents. The 25–34 yr age group had the highest prevalence of HIV, HCV, and HIV/HCV co-infections, reaching 24.4%, 26.2% and 16.0%, respectively. Overall, males had a much higher prevalence of all infections than females (HIV: 16.3% vs. 6.8%, HCV: 24.6% vs. 3.9%, HIV/HCV co-infected: 14.7% vs. 1.1%, respectively; P = 0.000). Approximately half of intravenous drug users tested positive for HIV (48.7%) and 68.4% tested positive for HCV. Logistic regression analysis showed that five factors were significantly associated with HIV and HCV infection: gender (odds ratio [OR]  = 5.8), education (OR = 2.29); occupation (student as reference; farmer: OR = 5.02, migrant worker: OR = 6.12); drug abuse (OR = 18.0); and multiple sexual partners (OR = 2.92). Knowledge of HIV was not associated with infection.
HIV and HCV prevalence in the Liangshan region is very serious and drug use, multiple sexual partners, and low education levels were the three main risk factors. The government should focus on improving education and personal health awareness while enhancing drug control programs.
PMCID: PMC4079678  PMID: 24988219

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